Viral infections are a major threat to human health and account for many serious infectious diseases. The most notable viruses are the blood-borne viruses (BBV), which include hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) which are all linked by their mode of transmission, ie. through blood or bodily fluids.
The Flaviviridae is a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. The Flaviviridae consists of various genera including:    1. Flaviviruses: This genus includes the Dengue virus, Japanese Tick-Borne and the Yellow Fever virus. Apart from these major groups, there are some additional Flaviviruses that are unclassified.    2. Hepaciviruses: This genus contains only one species, the Hepatitis C virus (HCV), which is composed of many genotypes and subtypes.
HCV is a major cause of viral hepatitis and has infected more than 200 million people worldwide. Current treatment for HCV infection is restricted to immunotherapy with interferon-α alone or in combination with ribavirin, a nucleoside analog. This treatment is effective in only about half the patient population. Therefore, there is an urgent need for new HCV drugs. Hepatitis C virus comprises a positive-strand RNA genome enclosed in a nucleocapsid and lipid envelope and consists of approximately 9600 ribonucleotides, which encodes a polyprotein of about 3000 amino acids (Dymock et al. Antiviral Chemistry & Chemotherapy 2000, 11, 79). A HCV protein, NS5B, released from the polyprotein, possesses polymerase activity and is involved in the synthesis of double-stranded RNA from the single-stranded viral RNA genome that serves as the template. The reproduction of HCV virus may be prevented through the manipulation of NS5B's polymerase activity. The inhibition of NS5B protein would suppress or prevent the formation of the double-stranded HCV RNA. Alternatively, a nucleoside analog also may be incorporated into the extending RNA strand and act as a chain-terminator. Furthermore, a deteriorating nucleoside analog also may be incorporated into the extending RNA, which may cause mutagenic damage to the viral genome. Recently, several PCT patent applications (WO 99/43691, WO 01/32153, WO 01/60315, WO 01/79246, WO 01/90121, WO 01/92282, WO 02/18404, WO 02/057287, WO 02/057425) have described nucleoside analogs as anti-HCV agents in in vitro assays.
HBV has acutely infected almost a third of the world's human population, and about 5% of the infected are chronic carriers of the virus (Delaney I V et al., Antiviral Chemistry & Chemotherapy 2001, 12, 1-35). Chronic HBV infection causes liver damage that frequently progresses to cirrhosis and/or liver cancer later in the life. Despite the availability and widespread use of effective vaccines and chemotherapy, the number of chronic carriers approaches 400 million worldwide. Therefore, more effective anti-HBV drugs need to be developed.
HIV causes progressive degeneration of the immune system, leading to the development of AIDS. A number of drugs have been used clinically, including reverse transcriptase inhibitors and protease inhibitors. Currently, combination therapies are used widely for the treatment of AIDS in order to reduce the drug resistance. Despite the progress in the development of anti-HIV drugs, AIDS is still one of the leading epidemic diseases.
Apart from the BBV's discussed above certain other acute viral infections also impose a great threat to human life, including the HSV, CMV, influenza viruses, West Nile virus, SARS virus, small pox, EBV, VZV and RSV. Accordingly, this highlights the continued need for the development of different antiviral drugs.
Bacterial infections have long been the sources of many infectious diseases. The widespread use of antibiotics has produced many new strains of life-threatening antibiotic resistant bacteria. Fungal infections are another type of infectious diseases, some of which also can be life-threatening. There is an ever increasing demand for the treatment of bacterial and fungal infections. As such, antimicrobial drugs based on new mechanisms of action are especially important.
Nucleoside drugs have been used clinically for decades for the treatment of viral infections and proliferative disorders such as cancer. Most of the nucleoside drugs are classified as antimetabolites. After they enter cells, nucleoside analogs are phosphorylated successively to nucleoside 5′-monophosphates, 5′-diphosphates, and 5′-triphosphates. In most cases, nucleoside triphosphates, e.g., 3′-azido-3′-deoxythymidine triphosphate (AZT, an anti-HIV drug) and arabinosylcytosine triphosphate (cytarabine, an anticancer drug), are the active chemical entities that inhibit DNA or RNA synthesis, through a competitive inhibition of polymerases and subsequent incorporation of modified nucleotides into DNA or RNA sequences. In a few cases, nucleoside analogs exert effects at lower phosphate levels. For instance, 5-fluoro-2′-deoxyuridine 5′-monophosphate (an anticancer drug) and 2′,2′-difluoro-2′-deoxycytidine 5′-diphosphate (an anticancer drug) have been shown to inhibit thymidylate synthase and ribonucleotide reductase, respectively. Although nucleoside analogs themselves may act at the nonphosphate level such as the inhibitors of adenosine kinases and the ligands of adenosine receptors, currently, clinically-useful nucleoside drugs primarily depend on cellular activation by nucleoside kinases and nucleotide kinases.
At least, two criteria are pertinent for nucleoside antiviral drugs: 1) nucleoside analogs should anabolise to nucleotides in cells; and 2) the anabolised nucleotides should target selectively viral enzymes. In order to be phosphorylated in cells and selectively target preferred enzymes, nucleoside analogs should have favourable modifications on their sugar and base moieties. To obtain such favourable nucleoside analogs, a general approach is to generate diverse nucleoside analogs by modifying the base or the sugar, or by modifying both base and sugar moieties. Numerous examples exist in the literature for the synthesis of a variety of modified nucleosides (Chemistry of Nucleosides and Nucleotides Vol. 1 (1988), Vol. 2 (1991), Vol. 3 (1994), edited by L. B. Townsend, Plenum Press; Handbook of Nucleoside Synthesis by H. Vorbrüggen and C. Ruh-Pohlenz, John Wiley & Sons, Inc., 2001; The Organic Chemistry of Nucleic Acids by Y. Mizuno, Elsevier, 1986).
However, there are certain classes of nucleoside compounds that were not explored intensively for their antiviral activities before the present invention. A class of such compounds is bicyclic nucleosides which are not derived from purine bases. Disclosures of bicyclic nucleosides are very limited considering that natural adenine and guanine (purines) based ribonucleotides and deoxy derivatives thereof, have bicyclic base moieties. WO 01/92282 A2, WO 01/90121 A2 and WO 04/058792 disclose derivatives of purine nucleosides. In contrast to these publications, the present invention discloses that a certain new class of bicyclic nucleosides and nucleotides display biological activity which may be particularly useful for the treatment of infectious diseases, including viral infections.